Oxygen is an environmental/developmental signal that regulates cellular energetics, growth, and differentiation processes. Despite its central role in nearly all higher life processes, the molecular mechanisms for sensing oxygen levels and the pathways involved in transducing this information are still being elucidated. Altering gene expression is the most fundamental and effective way for a cell to respond to extracellular signals and/or changes in its microenvironment. During development, the expression of specific sets of genes is regulated spatially (by position/morphogenetic gradients) and temporally, presumably via the sensing of molecular oxygen available within the microenvironment. Regulation of signaling responses is governed by transcription factors that bind to control regions (consensus sequences) of target genes and alter their expression in response to specific signals. Complex signal transduction during hypoxia (deficiency of oxygen in inspired gases or in arterial blood and/or in tissues) involves the coupling of ligand-receptor interactions to many intracellular events. These events basically include phosphorylations by tyrosine kinases and/or serine/threonine kinases, such as those of mitogen-activated protein kinases (MAPKs), a superfamily of kinases responsive to stress nonhomeostatic conditions. Protein phosphorylations imposed during hypoxia change enzyme activities and protein conformations, and the eventual outcome is rather complex, comprising of an alteration in cellular activity and changes in the programming of genes expressed within the responding cells. These molecular changes serve as signals that are crucial for cell survival under contingent conditions imposed during hypoxia. This review correlates current concepts of hypoxic sensing pathways with hypoxia-related phosphorylation mechanisms mediated by MAPKs via the genetic and pharmacologic regulation/manipulation of specific transcription factors and related cofactors.